Acyl desaturase enzymes catalyze the formation of a double bond in fatty acids derived from either dietary sources or de novo synthesis in the liver. In mammals, at least three fatty acid desaturases exists, each with differing specificity: delta-9, delta-6, and delta-5, which introduce a double bond at the 9-10, 6-7, and 5-6 positions respectively.
Stearoyl-CoA desaturases (SCDs) act with cofactors (other agents) such as NADPH, cytochrome b5, cytochrome b5 reductase, Fe, and molecular O2 to introduce a double bond into the C9-C10 position (delta 9) of saturated fatty acids, when conjugated to Coenzyme A (CoA). The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for further metabolism by fatty acid elongases or incorporation into phospholipids, triglycerides, and cholesterol esters. A number of mammalian SCD genes have been cloned. For example, two genes have been identified in humans (hSCD1 and hSCD5) and four SCD genes have been isolated from mouse (SCD1, SCD2, SCD3, and SCD4). While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat, R. et al., Eur. J. Biochem. (1979), Vol. 101, No. 2, pp. 439-445; de Antueno, R. et al., Lipids (1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directly implicated in human disease processes.
The two human SCD genes have been previously described: hSCD1 by Brownlie et al., PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety and hSCD2, PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety.
To date, the only small-molecule, drug-like compounds known that specifically inhibit or modulate SCD activity are found in the following PCT Published Patent Applications: WO 06/034338, WO 06/034446, WO 06/034441, WO 06/034440, WO 06/034341, WO 06/034315, WO 06/034312, WO 06/034279, WO 06/014168, WO 05/011657, WO 05/011656, WO 05/011655, WO 05/011654 and WO 05/011653. SCD inhibitors have also been described in by Zhao et al., Biorganic and Medicinal Chemistry Letters, 2007, and PCT Published Patent Applications WO 06/130986 and WO 07/009,236.
Before the discovery of the above compounds, only certain long-chain hydrocarbons, analogs of the substrate stearic acid, had been used to study SCD activity. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, cis-12, trans-10 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA, while cis-9, trans-11 isomer of conjugated linoleic acid does not have this biological activity. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2 octylcyclopropenyl)octanoic acid) and malvalic acid (7-(2-oclylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 position. These agents must be coupled to CoA to act as inhibitors and are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme complex, thus inhibiting delta-9 desaturation. Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a thioester moiety.
There is a major unmet need for small molecule inhibitors of SCD enzyme activity because evidence is now compelling that SCD activity is directly implicated in common human disease processes: See e.g., Attie, A. D. et al., “Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia”, J. Lipid Res. (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., “Role for stearoyl-CoA desaturase-1 in leptin mediated weight loss”, Science (2002), Vol. 297, No. 5579, pp. 240-3, Ntambi, J. M. et al., “Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity”, Proc. Natl. Acad. Sci. U.S.A. (2002), Vol. 99, No. 7, pp. 11482-6, Gutierrez-Juarez, R. et al. “Critical role of stearoyl CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance”, J. Clin. Invest. (2006), Vol 116, No. 6, pp. 1686-95, Dobrzyn A. and Dobrzyn P. “Stearoyl-CoA desaturase—a new player in skeletal muscle metabolism regulation”, J. Physiol Pharmacol. (2006), Vol 57 Suppl 10, pp. 31-42, Sampath, H. et al., “Stearoyl-CoA Desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat”, J. Biol. Chem., (2007), Vol. 282, No. 4, pp 2483-93, Xu H. et al., “Hepatic knockdown of stearoyl-CoA desaturase 1 via RNA interference in obese mice decreases lipid content and change sfatty acid composition”, Front. Biosci. (2007), Vol. 12, pp 3781-94.
The present invention solves this problem by presenting new drug-like classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.